CN115804907A

CN115804907A - Artificial cochlea drug-loading electrode and manufacturing, assembling and packaging methods thereof

Info

Publication number: CN115804907A
Application number: CN202211685217.1A
Authority: CN
Inventors: 王金剑; 周道民; 谭治平; 祁姝琪
Original assignee: Zhejiang Nurotron Biotechnology Co ltd
Current assignee: Zhejiang Nurotron Biotechnology Co ltd
Priority date: 2022-12-27
Filing date: 2022-12-27
Publication date: 2023-03-17

Abstract

The invention discloses a cochlear implant drug-loaded electrode and a manufacturing, assembling and packaging method thereof, wherein a flexible electrode tip in the cochlear implant electrode with a specific drug-loaded electrode structure is arranged at the foremost end of a silica gel body, n stimulation electrodes and m slow-release ports are all arranged on the silica gel body, a first boosting ring, a second boosting ring and an implantation fin are arranged behind the n stimulation electrodes and the m slow-release ports, a loop electrode is arranged at the tail end of the silica gel body, the stimulation electrodes are connected with a stimulation electrode lead, the stimulation electrode lead is connected with a loop electrode lead, a wave lead and a spiral lead are formed in the silica gel body, a drug cavity is arranged in the middle of the silica gel body, and a loading port is an inlet of the drug cavity and is arranged between the first boosting ring and the second boosting ring. The invention flexibly combines the medicine carrying component and the sustained-release component to realize the purpose of inner ear targeting and long-term sustained-release medicine treatment of a preoperative customizable treatment scheme.

Description

Artificial cochlea drug-loading electrode and manufacturing, assembling and packaging methods thereof

Technical Field

The invention relates to the field of medical instruments, in particular to a cochlear implant drug-loaded electrode and a manufacturing, assembling and packaging method thereof.

Background

Cochlear Implants (CI) is the main means for treating more than severe deafness at present, and has helped nearly 90 thousands of deaf people to regain hearing, so that patients are again incorporated into the society.

However, cochlear trauma caused by cochlear implant electrode insertion and pathological changes of the inner ear after implantation (such as inflammatory stimulation, fibroplasia, neuronal apoptosis, etc.) can damage the residual hearing before operation, and the application effect of the cochlear implant is affected. These cochlear tissue changes are derived from direct mechanical injury caused by electrode insertion, and are also related to mechanisms such as inflammatory response, apoptosis, etc. induced after implantation. Previous studies have shown that the application of the concept of "soft surgery", the selection of shorter and thinner, softer electrodes, slower, uniform implant electrodes and the use of perioperative steroids have a positive effect on hearing retention. However, there are still some patients who fail to maintain residual hearing after CI, or who gradually lose residual hearing within a few months after CI surgery. Therefore, relying solely on surgical technological advances and electrode design improvements is not sufficient to solve the above problems, and the combined use of drugs to prevent and treat cochlear implant rear inner ear pathology is a more effective solution.

Intravenous, intramuscular or oral administration remain the primary modes of administration for the treatment of inner ear diseases. Systemic treatment is not feasible for many drugs due to the blood-labyrinthine barrier between the inner ear and systemic blood circulation. In addition, systemic administration may cause adverse reactions to other organs of the body, or some patients with systemic diseases have contraindications to the drugs, such as patients with diabetes, hypertension, gastric ulcer, cannot be given systemic hormone therapy. The local administration of the inner ear leads the medicine to directly enter the inner ear by crossing the blood-labyrinth barrier, and the medicine concentration reached by the inner ear is more than 100 times of that of the systemic administration, thereby reducing the dosage, avoiding the adverse reaction of the systemic administration and improving the local effect of the medicine in the inner ear.

To date, direct or osmotic administration to the inner ear has been tympanogram perfusion, round window membrane sustained/controlled release, cochlear injection, and inner ear micro-pump administration, among others. The current main mode is tympanometry perfusion administration, and then sustained-release/controlled-release administration is carried out through a round window membrane, the two are theoretically based on the permeability of the round window membrane of the inner ear, and drug molecules reaching the middle ear cavity permeate into the inner ear through the round window membrane to play a role. However, the permeability of the round window membrane is affected by various factors, such as the size, configuration, concentration, lipid solubility, charge, thickness of the round window membrane, etc., and the permeable diameter of the round window membrane is less than 2 μm, and particles with a diameter of 3 μm or more cannot pass through. The cochlear injection has strict requirements on injection dosage and technology, mechanical and pressure injuries can be caused to cochlear fine structures by improper operation, and the benefit-risk ratio is not outstanding. The micro-pump for inner ear administration needs a micro-pump to provide power to deliver the drug to the inner ear, and the micro-pump also needs to be implanted in the body, and is expensive. Therefore, the above inner ear administration methods cannot achieve safe, continuous and stable maintenance of the inner ear drug concentration.

In recent years, the inner ear topical drug delivery regimen with cochlear implant electrodes as drug carriers has become a recent focus of research. The electrode consists of an electrode contact, an electrode wire and a silica gel substrate. According to related research reports at home and abroad, the improvement of the cochlear implant electrode mainly comprises electrode surface coating drug loading, electrode contact conductive polymer coating drug loading, silica gel matrix/slotted inlay drug loading and the like.

The drug loading of the surface coating has been reported in a large number of documents, and the research heat is high. The basic principle is as follows: after the active ingredients of the medicine, the polymer or the macromolecule and the volatile solvent are mixed evenly, the commercialized electrode is directly immersed into the solution for repeated dipping and air drying, so that a medicine-carrying coating is formed on the surface of the electrode, and the medicine in the coating is slowly released in a dissolving and diffusing mode to realize the treatment purpose. Commonly used polymers are poly-2-methacryloyl phosphorylcholine (PMPC), poly-L-lactic acid (PLLA), poly-4-hydroxybutyrate (P (4 HB)), poly (glycolide-co-lactide) (PLGA), polycaprolactone (PCL), polyethylene glycol (PEG), silicone rubber (PDMS), and the like. The coating drug loading is not only suitable for small molecule drugs, but also suitable for macromolecular drugs such as trophic factors, growth factors, proteins, stem cells and the like.

PMPC polymer is adopted as an electrode coating for drug loading in documents [ Kinoshita M, kikkawa Y S, sakamoto T, et al, safety, reliability, and operability of chlorine implant associated with biocompatible polymer [ J ]. Acta oto-laryngologica,2015,135 (4): 320-327 ]. Patent application number CN202010152071.9 discloses a preparation method of a high-molecular drug-loaded film and a drug-loaded electrode for artificial cochlea, the drug-loaded film can be quickly customized in the operation, the operability is strong, and the process is simple. However, the film has a small thickness (about 1 μm) and a low drug-loading rate (10-15 wt% of dexamethasone sodium phosphate and 1-2 wt% of cytarabine hydrochloride), so that the total drug amount is limited and long-term drug release is difficult to realize. And after the medicine-carrying coating is prepared, the film at the electrode contact point needs to be cleaned by a volatile solvent so as to expose the electrode contact point, so that the operation is complicated. Patent application No. CN202010713579.1 discloses an electrode drug-loaded coating with high drug-loading rate and a preparation method thereof, wherein 5-40 wt% of drug active ingredients are coated with a thickness of about 100 mu m, the total drug loading rate is high, and the electrode drug-loaded coating has a long-term drug release effect (270 days). However, how such a thick coating at the electrode contact is removed is not described herein, and a thicker coating will significantly increase the size of the original electrode, resulting in increased insertion force and increased surgical difficulty during electrode implantation. Patent application No. CN201710083677.X discloses a method for coating a medicine-carrying gel coating on the surface of a cochlear implant electrode by using an open constant-pressure injector, wherein the coating is flat and uniform, and the total medicine amount can reach 55mg. However, the coating method produces a coating layer having significantly lower adhesion between the electrode than the immersion method, and also requires an increase in the thickness of the coating layer to increase the total amount of the drug. Patent application numbers CN201880011109.1 and CN201880011117.6 disclose a preparation method of an implantable electrode of a silicone drug-carrying coating, the drug-carrying amount in the coating is 10-20 wt%, and the drug release rate can be adjusted and controlled by changing the heat treatment parameters during curing of the silicone. However, the drug loading is low, the release period is short (30 days), and the rapid customization before or during the operation is difficult, and the operability is poor. In order to improve the adhesion between the coating and the electrode, patent application No. CN201480049147.8 adopts a mechanical connection mode to fix the drug-loaded gel coating on the electrode, and the gel coating expands when contacting lymph fluid without falling off. Chemical modification of the electrode surface in the literature [ Bohl A, rohm H W, ceschi P, et al, development of a specific functionalized local drug delivery system for the prevention of fibrous injury of fibrous implants within the inner electrode [ J ]. Journal of Materials Science Materials in Medicine,2012,23 (9): 2151-2162 ] allows drug molecules to attach to the electrode surface via L-polylactic acid (PLLA) and be slowly released following the degradation of PLLA after reaching the target, in vitro experiments confirm the safety of drugs and PLLA degradation products to nerve cells. However, the core of the method is chemical reaction, complex surface activation and crosslinking are needed, the formed coating is firm, but the drug release behavior cannot meet the requirement, the cost is increased, and the clinical conversion is difficult to realize.

The basic principle of electrode contact drug loading is as follows: in the conductive polymer monomer solution containing the drug, the electrochemical polymerization method is used for carrying the drug on the electrode contact in situ polymerization reaction, and the electrical stimulation is used for controlling the drug release. Patent application No. CN202010493169.0 discloses an electric polymerization conductive polymer drug-loaded cochlear implant electrode and a manufacturing method thereof, ear drugs and conductive polymer are solidified on a substrate through electric polymerization chemical reaction, and the release of the drugs is controlled by electric quantity applied to a drug film electrode. The medicine can not be freely diffused during the release, and the physical and chemical properties of the electrode array silicon colloid can not be changed, so that the functionality and the reliability of the cochlear implant electrode can not be influenced. However, the electrode contact has a limited area and the coating has a thin thickness, so that the drug loading is low and the long-term drug therapy requirement is difficult to meet.

The silica gel matrix/slot inlay drug loading is largely divided into three categories: silica gel matrix drug loading, inlay drug loading, sleeve drug loading. The principle of silica gel matrix drug loading is as follows: the medicine is mixed in the silica gel raw material used by the cochlear implant electrode, and the silica gel body of the cochlear implant electrode is prepared by the silica gel raw material containing the medicine components. The principle of inlaying the medicine carrying is as follows: a medicine carrying groove is carved on a silica gel body of the existing cochlear implant electrode by processes such as laser and the like, and an mosaic body containing medicine is loaded in the groove. The principle of sleeve medicine carrying is: a drug-containing cartridge is prepared and loaded onto an existing cochlear implant electrode.

The slow release behavior of dexamethasone (0.25-2.0 wt%) embedded in a silica gel matrix was studied in the literature [ Ghavi F, mirzadeh H, imani M, et al. Experimental study of cochlear effect by liu ya novel drug-loaded electrode [ D ] science and technology university in huazhong, 2008 ] the pharmacokinetics of silica gel matrices with 2.0 and 10wt% drug loading were studied. It was found that although the drug loading of the silica gel matrix is generally not high (< 10 wt%), the total drug loading is considerable due to the large size of the silica gel, long-term dosing can be achieved, and the total drug loading can be further increased by increasing the drug loading. However, it should be noted that as the drug is dissolved, the silica gel matrix gradually forms pores of different sizes, which destroys the integrity of the electrode surface and may impair the performance of the electrode to some extent. The drug in the silica gel matrix is mostly in the form of crystals, and is coarse, which can cause large implantation wounds in the process of implanting the electrode. Thus, increasing the drug loading increases the total drug loading, but is also accompanied by an increase in the risk of adverse events such as pinholes and surface roughness. The solubility of the drug in silica gel is not high, the operability of the process needs to be considered, and the space for increasing the total drug amount by improving the drug loading amount is limited. In addition, only small molecular drugs such as glucocorticoid (such as dexamethasone) are reported at present in the drug loading of the silica gel matrix.

In patent publications WO2009029866A3 and US2013079749A1, advanced Bionics LLC discloses a cochlear implant electrode with drug loading embedded inside/on the shallow surface of the electrode, and a polymer film coated on the surface of the inlay is used to control the drug release behavior. Literature [ Robert B, stephen O L, catherine B, et al. Comparison of electrode impedance measures between a dexmethasone-exciting and a standard code ^TM Contour

electrode in adult cochlear implant recipients[J].Hearing Research,2020,390:107924.]In the research on the drug release behavior of a drug-loaded electrode containing a drug-loaded inlay in the similar silica gel and at the tip of the electrode, the result shows that the drug release concentration after 42 days is lower than the therapeutic concentration window although the drug loading amount is up to 40 wt%. The embedded medicine carrying needs to be placed into an embedding body when the cochlear implant electrode is prepared, the customized cochlear implant electrode is needed, and flexible assembly in the operation can not be realized to adapt to different treatment schemes. In order to solve the problem that the medicine-carrying mosaic body needs to be put in advance and is difficult to flexibly assemble, the mosaic body can be arranged on the surface of the electrode. Patent publication No. WO2013108234A1 discloses a method of using a drug-loaded inlay to replace part of the silica gel on the surface of an electrode to carry drug to the electrode, so that the inlay can be placed in a later stage. In patent application nos. CN200780008385.4 and CN200780027561.9, MED-EL Elektromed geraetee GmbH also discloses a similar way to the above, embedding a drug carrier inside or on the surface of the electrode, and has similar advantages and disadvantages. The drug loading amount of the mosaic drug is determined by the carrier used by the mosaic body, and the total drug amount is determined by the drug loading amount, the volume and the quantity of the mosaic body. Simply increasing the volume and number of inlays may achieve an increase in the total drug dose, but the use of large area inlays will change the overall electrode structure and characteristics with associated risks.

In patent application number CN201180036177.1, cochlear Limited discloses a sleeve drug-loading mode, namely, a drug-containing sleeve is prepared, and the sleeve is loaded on an electrode to realize drug loading. The drug loading mode is flexible, the drug loading type can be selected, and the influence on the existing electrode structure is avoided. The disadvantage is that the sleeve increases the overall size of the electrode, which can lead to implantation trauma with increased implantation force, and it is not known whether the sleeve will fall off during surgical implantation or drug treatment.

The above prior art has defects, and the inner ear local drug delivery scheme for carrying out drug loading on the surface of the electrode by using the polymer coating has the characteristic of strong operability, and can be realized on a commercialized cochlear implant electrode without specially customizing the electrode. However, to ensure the smoothness and uniformity of the coating on the electrode, the viscosity of the polymer solution containing the drug is required and limited by the solubility limit of different drugs, and the drug loading of the coating is often low (< 50 wt%), so that the total drug loading can be increased only by increasing the coating thickness to realize long-term drug release. However, the increase of the thickness of the coating inevitably leads to the increase of the size of the electrode, increases the difficulty of the operation and brings safety risks. The polymer solution contains more volatile solvents, which leads to a very high tendency of the finished coating to crack. The coating drug loading is often applied to the whole electrode, and how to effectively, controllably and thoroughly remove the redundant coating on the electrode contact to expose the electrical stimulation part still has great challenge, especially for thicker coatings. The coating is often wrapped on the electrode in a physical adhesion mode, the adhesion is poor, and the coating has a falling risk in the implantation operation process or the drug release process after the operation. The coating usually adopts biodegradable polymer as a drug carrier, burst release exists in the early stage of drug release, and the influence of degradation products on the microenvironment of the inner ear and related safety are not clear yet. Finally, the drug loading mode is often used for loading a single variety of drugs, and combination therapy and staged therapy of multiple drugs are difficult to realize.

The inner ear drug delivery scheme for carrying out drug loading on the electrode contact by the conductive polymer coating has the advantages of good coating quality, accurate drug release, unchanged functionality and reliability of the electrode and the like. However, the area of the electrode contact is limited, and the coating thickness is thin, so that the drug loading is low, and the long-term drug therapy requirement is difficult to meet. Most conductive polymers are not degradable, and need to be taken out after being implanted into a body through a subsequent operation, so that the pain of a patient is increased, and the wide use is not facilitated. Finally, the variety of drugs to which this method is applicable is limited.

The silica gel matrix/internal embedded drug loading can realize high drug loading and long-term drug release. However, drug-loaded electrodes need to be customized and cannot be flexibly loaded, and the characteristics of the surface of the colloidal silica/electrode change, especially with the safety risks associated with the continuous dissolution of the drug, the types of the loaded drug are also limited. Although the surface of the silica gel body is embedded with the medicine carrying, the assembly can be flexibly carried out, but the risk of falling of the embedded body exists. The sleeve carries medicine and does not change the structure of the existing electrode, and can be assembled flexibly. A disadvantage is that the sleeve increases the overall size of the electrode, leading to implantation trauma with increased implantation force and the risk of the sleeve falling off during surgery or treatment.

Disclosure of Invention

The invention aims to solve the technical problems that the pathological changes of the inner ear after the implantation of the cochlear implant can damage the effect of auditory reconstruction and the residual hearing before operation, and the prior art has the defects of low drug loading, difficult realization of long-term treatment, weak adhesion and easy falling of a coating, influence on the long-term stability and reliability of an electrode due to the change of physicochemical properties of a silica gel matrix, an electrode contact and the surface of the electrode, single drug loading, special customization, uncontrollable drug release behavior, difficult clinical application conversion and the like. The invention provides a novel cochlear implant drug-loaded electrode containing a drug-loaded component and a slow-release component, the novel cochlear implant drug-loaded electrode does not change the body and surface characteristics of the existing electrode, each component is independently prepared, produced, sterilized and packaged, each component can be flexibly combined and rapidly assembled in a customized manner according to a treatment scheme before operation, the drug release behavior can be regulated and controlled, the combined treatment of multiple drugs and different treatment periods (short, medium and long-term) requirements are supported, and the conditions of residual hearing loss and the like caused by postoperative inner ear inflammation, fibrosis and other pathological changes can be effectively improved. The preparation method of each component in the cochlear implant drug-loaded electrode with simple process is also provided, and the assembly and encapsulation methods and the application of the cochlear implant drug-loaded electrode are also provided.

In order to achieve the purpose, the technical scheme of the invention is as follows: a cochlear implant drug-carrying electrode comprises a cochlear implant electrode with a specific structure, a drug-carrying component and a release component, wherein the cochlear implant electrode with the specific structure comprises a flexible electrode tip, n stimulation electrodes, m release ports, 1 loading port, 1 drug cavity, a silica gel body, a first boosting ring, a second boosting ring, an implanted fin, a wave guide wire harness, a spiral guide wire harness, a loop electrode, a stimulation electrode lead and a loop electrode lead; the shape of the slow release port is matched with that of the slow release component, and the inner diameter of the slow release port is larger than the outer diameter of the slow release component.

Preferably, the relative positions of the stimulating electrodes and the sustained-release ports are in the same alignment, staggered alignment or staggered alignment.

Preferably, the inner diameter of the medicine cavity is 0.01-0.05 mm larger than the outer diameter of the medicine carrying part, and the inner diameter of the slow release opening is 0.01-0.05 mm larger than the outer diameter of the slow release part.

Preferably, the medicine-carrying part comprises 5-95 wt% of medicine active ingredients, 5-95 wt% of medicine-carrying polymer and 0-10 wt% of medicine-carrying auxiliary agent; the slow release component comprises 70-100 wt% of slow release polymer and 0-30 wt% of slow release auxiliary agent.

Preferably, the pharmaceutically active ingredient is selected from one or a combination of cortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisone, prednisolone, methylprednisolone, prednisolone dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, clobetasone butyrate, betamethasone valerate, betamethasone dipropionate, beclomethasone propionate, clobetasol propionate, fluorometholone, halomethasone, flumethasone pivalate, mometasone furoate, flurandrenolide, fluocinonide acetate, triamcinolone acetonide, halcinonide, amcinonide, desonide, budesonide, fluticasone, deflazacort, cytarabine hydrochloride, adenine dinucleotide dinuclear nucleotide, and one or a combination thereof, and insulin-like growth factor, hepatocyte growth factor, brain-derived neurotrophic factor, laminin, peptide inhibitor, or a combination thereof.

Preferably, the drug-loaded polymer and the sustained-release polymer are both biocompatible and non-degradable or degradable, and are selected from one or more of polylactide, polyglycolide, glycolide-lactide copolymer, polyethylene glycol, polycaprolactone, poly-L-lactic acid, poly-4-hydroxybutyrate and silicone rubber.

Preferably, the drug loading aid and the sustained-release aid are both release regulators or pore-forming agents, and are selected from one or more of hydroxypropyl methylcellulose, hyaluronic acid and sodium salt thereof, poloxamer, polyethylene glycol, polyether, polyvinyl alcohol, polyvinylpyrrolidone, lactose, mannitol, glucose, maltose, sorbitol, sodium dodecyl sulfate, sodium chloride, potassium chloride, magnesium carbonate, sodium bicarbonate, potassium bicarbonate or sucrose.

Based on the above purpose, the invention also provides a manufacturing method of the cochlear implant drug-loaded electrode, which comprises the following steps,

s10, manufacturing a cochlear implant electrode with a specific structure;

s20, manufacturing a medicine carrying part;

s30, manufacturing a slow release component;

s10, manufacturing the cochlear implant electrode with the specific structure, which comprises the following steps:

s11, manufacturing a stimulation electrode and a stimulation electrode lead, and welding the stimulation electrode and the stimulation electrode lead;

s12, performing wave-shaped and spiral treatment on the stimulating electrode lead bundle to prepare a wave lead bundle and a spiral lead bundle;

s13, manufacturing a loop electrode and a loop electrode lead, and welding the loop electrode and the loop electrode lead;

s14, fixing the components in a mold, injecting biocompatible silicon rubber, and taking out the components from the mold after curing;

s15, sterilizing and packaging;

s20, manufacturing a medicine carrying component, which comprises the following steps:

s21, weighing a medicine active ingredient, a medicine carrying polymer and a medicine carrying auxiliary agent in a container according to a preset weight percentage;

s22, placing the container into a planetary stirrer, carrying out centrifugal stirring and vacuum defoaming;

s23, injecting the uniformly mixed and defoamed mixture into a mold, and performing compression molding;

s24, sterilizing and packaging;

s30, manufacturing a slow-release component, comprising the following steps:

s31, weighing a sustained-release polymer and a sustained-release auxiliary agent in a container according to a preset weight percentage;

s32, placing the container into a planetary stirrer, carrying out centrifugal stirring and vacuum defoaming;

s33, injecting the uniformly mixed and defoamed mixture into a mold, and performing injection molding;

and S34, sterilizing and packaging.

Based on the above purpose, the invention also provides an assembly and encapsulation method of the cochlear implant drug-loaded electrode, which comprises the following steps:

s1, loading a medicine carrying part into a medicine cavity from a loading port, and coating a moisture-curing silicone rubber adhesive to form an isolation film;

s2, repeating S1 until the medicine cavity is filled with full medicine components;

s3, coating a moisture-curing silicone rubber adhesive on the surface of the slow-release component, and filling the slow-release component into a slow-release opening;

s4, repeating S3 until the slow release port is filled with a slow release component;

and S5, curing the adhesive.

Preferably, after the medicine carrying part is loaded, the loading port is packaged by a packaging body, and the packaging body is a screw cap or a plug made of biocompatible silicone rubber.

The invention does not change the characteristics of the colloidal silica body and the electrode surface of the existing cochlear implant electrode, the medicine carrying part and the cochlear implant electrode are independently prepared, produced and sterilized, the medicine carrying quantity and the total medicine quantity are high, the applicable medicine types are wide, the medicine types, the medicine carrying quantity and the total medicine quantity can be quickly and flexibly customized and controlled to release medicine before operation according to a treatment scheme, the implantation, the electrical stimulation or the treatment process is safe and reliable, and the requirements of combination treatment, staged treatment and different treatment periods of various medicines are supported.

The method at least comprises the following beneficial effects:

1. the drug loading capacity and the total drug loading capacity of the cochlear implant drug-loaded electrode can be flexibly regulated and controlled, the maximum drug loading capacity reaches 95wt%, short, medium and long-term drug targeted treatment of the inner ear can be realized, and the cochlear implant drug-loaded electrode has a simple preparation process and is easy for industrial production and clinical conversion application;

2. the cochlear implant electrode, the drug-loading component and the sustained-release component with the specific structure are independently prepared and produced and are assembled before the operation, so that the adaptive sterilization and packaging mode can be selected according to the characteristics of each component (especially the characteristics of the drug), and the influence of the sterilization mode on the stability and the efficacy of the drug is avoided;

3. the drug-loading component is assembled in the electrode, and the silica gel substrate, the electrode contact, the electrode surface characteristics (such as roughness, chemical components, structure and the like) and the like are the same as those of the conventional artificial cochlea electrode, so that the long-term reliability and safety of the electrode and the effectiveness of electrical stimulation cannot be influenced;

4. when the device is assembled, different drug types and drug-loading parts with drug-loading capacity can be flexibly selected, so that single-variety drug therapy can be realized, and multiple drugs can be combined for therapy;

5. according to the clinical treatment scheme, the medicine-carrying component and the sustained-release component which are adaptive are selected for assembly, the medicine release characteristic is easy to regulate and control, the regulation and control range is wide, the medicine release concentration, speed and period can be controlled, and customized treatment is realized.

Drawings

Fig. 1 is a schematic structural diagram of a cochlear implant electrode according to an embodiment of the invention;

FIG. 2 is a schematic cross-sectional view of a cochlear implant electrode according to an embodiment of the present invention;

fig. 3 is a schematic structural diagram of a cochlear implant electrode with a specific structure, in which three typical arrangement modes of a stimulating electrode and a sustained-release port of the cochlear implant electrode according to the embodiment of the invention are provided;

fig. 4 is a schematic structural diagram of two typical medicine-carrying parts of a cochlear implant medicine-carrying electrode according to an embodiment of the invention;

FIG. 5 is a schematic diagram of two exemplary slow release components of a cochlear implant electrode according to an embodiment of the present invention;

FIG. 6 is a schematic diagram of the steps of an assembly and encapsulation method of a cochlear implant electrode according to an embodiment of the invention;

fig. 7 is a graph of drug release data of cochlear implant drug-carrying electrodes combined by different drug-carrying parts and slow-release parts of cochlear implant drug-carrying electrodes according to embodiments of the present invention;

fig. 8 is a flow chart of the clinical application of the cochlear implant electrode according to the embodiment of the invention.

Detailed Description

Referring to fig. 1, the cochlear implant drug-loaded electrode comprises a cochlear implant electrode with a specific structure, a drug-loaded component 6 and a release component 5, wherein the cochlear implant electrode with the specific structure comprises a flexible electrode tip 1, n stimulation electrodes 4,

m release ports

3, 1

loading port

10, 1 drug cavity 2, a silica gel body 8, a first boosting ring 11, a second boosting ring 12, an implanted fin 13, a wave lead 14, a spiral lead 15, a loop electrode 16, a stimulation electrode lead 17 and a loop electrode lead 18. The flexible electrode tip 1 is arranged at the foremost end of the silica gel body 8, the n stimulation electrodes 4 and the m slow release ports 3 are all arranged on the silica gel body 8, the n stimulation electrodes 4 and the m slow release ports 3 are arranged to be aligned to be identical, aligned to be staggered or aligned to be staggered, a first boosting ring 11, a second boosting ring 12 and an implantation fin 13 are arranged behind the n stimulation electrodes 4 and the m slow release ports 3, the loop electrodes 16 are arranged at the tail end of the silica gel body 8, the stimulation electrodes 4 are connected with stimulation electrode leads 17, the loop electrodes 16 are connected with loop electrode leads 18, the stimulation electrode leads 17 form a wave lead 14 and a spiral lead 15 in the silica gel body 8, the medicine cavity 2 is arranged in the middle of the silica gel body 8, the loading port 10 is an inlet of the medicine cavity 2 and is arranged between the first boosting ring 11 and the second boosting ring 12.

The shape of the medicine cavity 2 is matched with that of the medicine carrying part 6, and the inner diameter is larger than the outer diameter of the medicine carrying part 6. The shape of the slow release port 3 is matched with that of the slow release component 5, and the inner diameter is larger than the outer diameter of the slow release component 5. In a specific embodiment, the size of the medicine cavity 2 is 0.01-0.05 mm larger than that of the medicine carrying part 6, and the size of the slow release port 3 is 0.01-0.05 mm larger than that of the slow release part 5.

The manufacturing method of the artificial cochlea electrode with the specific structure comprises the following steps: manufacturing a stimulation electrode 4 and a stimulation electrode lead 17, and welding the stimulation electrode 4 and the stimulation electrode lead 17; carrying out wave-shaped and spiral treatment on the stimulating electrode lead bundle to prepare a wave lead bundle 14 and a spiral lead bundle 15; manufacturing a loop electrode 16 and a loop electrode lead 18, and welding the loop electrode 16 and the loop electrode lead 18; fixing the above components in a mold, injecting biocompatible silicone rubber, curing, taking out from the mold, sterilizing, and packaging.

The drug-carrying part 6 comprises a drug active ingredient, a drug-carrying polymer and a drug-carrying assistant, and in a specific embodiment, the drug active ingredient comprises 5-95 wt% of the drug active ingredient, 5-95 wt% of the drug-carrying polymer, and 0-10 wt% of the drug-carrying assistant, preferably 20-90 wt% of the drug active ingredient, preferably 60-80 wt% of the drug active ingredient, and the drug active ingredient is uniformly dispersed in the drug-carrying polymer. Further, the drug carrying member 6 is rod-shaped, and the cross section thereof is circular, oval, quadrilateral, triangular or other suitable shape, preferably circular. The diameter is 0.1 to 0.6mm, preferably 0.2 to 0.4mm. The diameters of both ends are the same or increase stepwise, preferably stepwise. The length is 2 to 30mm, preferably 5 to 10mm.

The drug-carrying polymer is biocompatible, non-degradable or degradable, and is selected from one or more of Polylactide (PLA), polyglycolide (PGA), glycolide-lactide copolymer (PLGA), polyethylene glycol (PEG), polycaprolactone (PCL), poly-L-lactic acid (PLLA), poly-4-hydroxybutyrate (P (4 HB)), and silicone rubber (PDMS), preferably PLGA, PCL, PDMS, preferably PDMS.

The drug-loading auxiliary agent is a release regulator/pore-forming agent, and is selected from one or more of hydroxypropyl methylcellulose, hyaluronic acid and sodium salt thereof, poloxamer, polyethylene glycol, polyether, polyvinyl alcohol, polyvinylpyrrolidone, lactose, mannitol, glucose, maltose, sorbitol, sodium dodecyl sulfate, sodium chloride, potassium chloride, magnesium carbonate, sodium bicarbonate, potassium bicarbonate or sucrose, preferably polyethylene glycol, mannitol, sodium chloride and polyvinylpyrrolidone, and preferably mannitol, sodium chloride and polyvinylpyrrolidone.

<xnotran> , , , , , , , , , (DA), (DSP), , , , , , , , , , , , , , , , , , , , , , , , (Ara-C), , , (IGF), (HGF), (BDNF), , , , , , , , , , . </xnotran> Further, pharmaceutically active ingredients also include salts and esters that may be used, such as, but not limited to, acetic acid, butyric acid, sodium succinate, diacetate, phosphoric acid, propionic acid, hydrochloride or ester, sulfate, phosphate, hydrochloride, lactobionate, aspartate, nitrate, citrate, purine or pyrimidine salts, maleate, and the like.

The manufacturing method of the medicine carrying part 6 comprises the following steps: the medicine active ingredients, the medicine carrying polymer and the medicine carrying auxiliary agent are physically and uniformly mixed according to corresponding proportion, the mixture is solidified into the medicine carrying part 6 with a specific structure by a hot melt extrusion, injection molding or compression molding method, and the medicine carrying part is sterilized and packaged. Furthermore, a suitable preparation method is selected according to the characteristics of the active pharmaceutical ingredient and the drug-loaded polymer.

The components of the slow release component 5 comprise a slow release polymer and a slow release assistant, and in a specific embodiment, the slow release polymer comprises 70-100 wt% of the slow release polymer, 0-30 wt% of the slow release assistant, and preferably 2-10 wt% of the slow release assistant. Further, the sustained-release member 5 is a rod-like member, and the cross-sectional shape thereof is circular, oval, quadrangular, triangular or other suitable shape, preferably circular. The diameter is 0.05 to 0.5mm, preferably 0.1 to 0.3mm. The diameters of both ends are the same or increase stepwise, preferably the same. The length of which is equal to or less than the depth of the sustained release port 3.

The sustained-release polymer is biocompatible, non-degradable or degradable, and is selected from one or more of Polylactide (PLA), polyglycolide (PGA), glycolide-lactide copolymer (PLGA), polyethylene glycol (PEG), polycaprolactone (PCL), poly-L-lactic acid (PLLA), poly-4-hydroxybutyrate (P (4 HB)), and silicone rubber (PDMS), preferably PLGA, PCL, PDMS, preferably PDMS.

The slow release auxiliary agent is release regulator/pore-forming agent selected from one or more of hydroxypropyl methylcellulose, hyaluronic acid and its sodium salt, poloxamer, polyethylene glycol, polyether, polyvinyl alcohol, polyvinylpyrrolidone, lactose, mannitol, glucose, maltose, sorbitol, sodium dodecyl sulfate, sodium chloride, potassium chloride, magnesium carbonate, sodium bicarbonate, potassium bicarbonate or sucrose, preferably polyethylene glycol, mannitol, sodium chloride, polyvinylpyrrolidone, preferably mannitol, sodium chloride, polyvinylpyrrolidone.

The manufacturing method of the sustained-release component 5 comprises the following steps: the slow release polymer and the slow release auxiliary agent are physically and uniformly mixed according to corresponding proportion, the mixture is solidified into the slow release part 5 with a specific structure by a hot melt extrusion, injection molding or compression molding method, and the mixture is sterilized and packaged. Further, an appropriate preparation method is selected according to the characteristics of the mixture.

According to the assembling and packaging method of the cochlear implant drug-loaded electrode, the drug-loaded component 6 with corresponding drug type and drug content is selected according to a preoperative treatment scheme, the sustained-release component 5 with corresponding porosity is selected according to the drug release rate, and the drug-loaded component 6, the sustained-release component 5, the packaging body 9 and the cochlear implant electrode are assembled and packaged. The method comprises the following specific steps: the medicine-carrying component 6 is sequentially loaded into the medicine cavity 2 of the cochlear implant electrode from the loading port 10, the loading port 10 is packaged by the packaging body 9, the surface of the slow-release component 5 is coated with moisture-cured silicone rubber adhesive and is loaded into the slow-release port 3 of the cochlear implant electrode, and the adhesive is cured. Further, when a plurality of medicine carrying parts 6 are contained in the medicine cavity 2, moisture-curing silicone rubber adhesive can be coated on the upper surface and the lower surface of the medicine carrying parts 6 so as to form an isolating membrane 7 between the parts.

Further, the packaging body 9 is a moisture-curable silicone rubber adhesive, and is injected and cured on site after the medicine-carrying part 6 is loaded; alternatively, the packaging body 9 is a screw cap or a plug made of a conventional biocompatible silicone rubber material, and is installed after the drug-carrying part 6 is loaded.

The artificial cochlea drug-loaded electrode also comprises a method for controlling the drug release behavior based on the artificial cochlea drug-loaded electrode, wherein the burst release at the early stage is small, the drug release at the middle stage is stable, the drug release at the later stage is slow, the drug concentration and the drug release period are controlled by the drug-loaded quantity of the drug-loaded component 6, the time for releasing 90wt% of the drug is 20-700 days, and the drug release rate is controlled by the porosity of the slow-release component 5.

Still include based on the application of above-mentioned cochlear implant medicine carrying electrode, because a plurality of medicine carrying parts 6 can be loaded in medicine chamber 2, the medicine carrying part 6 of selecting single medicine type loads medicine chamber 2 and can realize single drug therapy, the medicine carrying part 6 of selecting two kinds or multiple medicine types loads medicine chamber 2 and can realize many medicines combined therapy. Furthermore, the target treatment position is related to the selected nerve stimulation electrode, such as the artificial cochlea medicament-carrying electrode can treat the inner ear diseases, and such as the brain nerve stimulation medicament-carrying electrode can treat the brain diseases, preferably the inner ear diseases. Further, the disease to be treated is related to the type of drug selected, preferably post-implantation fibrosis and inflammation treatment.

The present application will be described in detail with reference to specific examples, but the present application is not limited to these examples.

Referring to fig. 1 and 2, a cochlear implant electrode of a specific structure is manufactured as follows:

s11, manufacturing a stimulation electrode 4 and a stimulation electrode lead 17, and welding the stimulation electrode 4 and the stimulation electrode lead 17;

s12, performing wave-shaped and spiral treatment on the stimulating electrode lead bundle to form a wave lead bundle 14 and a spiral lead bundle 15;

s13, manufacturing a loop electrode 16 and a loop electrode lead 18, and welding the loop electrode 16 and the loop electrode lead 18;

s14, fixing the components in a mold, injecting biocompatible silicon rubber 8, and taking out the components from the mold after curing;

s15, sterilizing and packaging.

In the specific embodiment:

the preparation process of the stimulating electrode 4 in the S11 comprises the following steps: annealing and rolling the platinum-iridium alloy blank into a platinum-iridium alloy sheet; and (3) performing laser cutting on the platinum-iridium alloy sheet, and performing punch forming.

The preparation process of the stimulation electrode lead 17 in the step S11 comprises the following steps: annealing, cold-drawing and straightening the platinum-iridium alloy blank to obtain a platinum-iridium alloy wire; coating, wave-shaped and spiral treatment are carried out on the platinum-iridium alloy wire; and (3) cutting a platinum-iridium alloy wire, and removing coatings at two ends.

The preparation process of the loop electrode 16 in the step S13 is as follows: annealing, cold-drawing, straightening and polishing the platinum-iridium alloy blank to form an annular platinum-iridium alloy sheet; and carrying out laser cutting and deburring on the platinum-iridium alloy sheet.

The preparation process of the loop electrode lead 18 in the step S13 is as follows: annealing, cold-drawing and straightening the platinum-iridium alloy blank to obtain a platinum-iridium alloy wire; and (3) cutting a platinum-iridium alloy wire, and removing coatings at two ends.

The silicon rubber used in S14 is liquid silicon rubber, the curing temperature is 100-150 ℃, and the curing time is 0.5-3 h.

In the die used in S14, the cross-sectional shapes of the drug cavity and the sustained-release port are circular, the diameter of the proximal end of the drug cavity is 0.25mm, the diameter of the distal end is 0.45mm, and the length is 20mm. The proximal end of the slow release port has a diameter of 0.06mm, the distal end has a diameter of 0.16mm, the depth is 0.1-0.2 mm, and the slow release port needs to penetrate through the medicine cavity.

In the mold used in S14, the cavity is located in the middle. The same contraposition of the sustained-release port 3 and the stimulation electrode 4 is the cochlear implant electrode E1, the contraposition of the sustained-release port 3 and the stimulation electrode 4 is staggered to be the cochlear implant electrode E2, the contraposition of the sustained-release port 3 and the stimulation electrode 4 is staggered to be the cochlear implant electrode E3, referring to fig. 3, 31, 32 and 33 in fig. 3 are different relative positions of the sustained-release port 3 and the stimulation electrode 4 of three embodiments, specifically referring to table 1:

TABLE 1 cochlear implant electrode number, position and size

The manufacturing method of the medicine carrying part 6 comprises the following steps:

referring to fig. 4 showing the medicated component 6, fig. 4 shows two embodiments of medicated component 6 at 61 and 62, made as follows:

s21, weighing the active pharmaceutical ingredients, the drug-loaded polymer and the drug-loaded auxiliary agent in the container according to the corresponding weight percentage;

s23, injecting the uniformly mixed and defoamed mixture into a mold, and pressing and molding;

and S24, sterilizing and packaging.

In the specific embodiment: the types and the content percentage of each component in the S21 are shown in the table 2:

TABLE 2 composition and size of drug loaded parts

The stirring speed in S22 is 2000-4000 rpm, and the time is 0.5-5 min.

The size of the mold cavity in S23 is as shown in the table above.

The curing temperature of the compression molding in the S23 is 100-150 ℃, and the curing time is 0.5-3 h.

Referring to the sustained release member 5 shown in fig. 5, fig. 5 shows sustained release members 5 of two embodiments, 51 and 52, which are prepared as follows:

s31, weighing the sustained-release polymer and the sustained-release auxiliary agent in a container according to the corresponding weight percentage;

and S34, sterilizing and packaging.

In the specific embodiment: the types and the content percentages of the components in the S31 are shown in the following table 3:

TABLE 3 composition and size of the sustained Release Components

The stirring speed in S32 is 2000-4000 rpm, and the time is 0.5-5 min.

The size of the mold cavity in S33 is as shown in the table above.

The curing temperature of the injection molding in the S33 is 100-150 ℃, and the curing time is 0.5-3 h.

The assembling and packaging method of the cochlear implant drug-loaded electrode comprises the following steps:

referring to the process schematic of fig. 6, the preparation process is as follows:

s1, loading a medicine carrying part 6 into a medicine cavity 2 from a loading port 10, and coating a small amount of moisture-curing silicone rubber adhesive to form an isolation film 7;

s3, coating a small amount of moisture-curing silicone rubber adhesive on the surface of the slow-release component 5, and filling the slow-release component into the slow-release port 3;

s4, repeating the step S3 until the slow release port 3 is filled with the slow release component 5;

and S5, curing the adhesive.

In the specific embodiment:

the last time of applying the adhesive in S2 is to fill the loading opening 10 to form the package 9.

The curing conditions in S5 are a temperature of 15 to 30 ℃, a humidity of 40 to 60% RH, and a curing time of 2 to 24 hours.

See table 4 for specific examples:

table 4 example compositions of cochlear implant drug-loaded electrodes

In vitro release experiments:

putting the groups of cochlear implant electrode into corresponding sample bottles respectively, and adding 4mL of release medium (artificial perilymph liquid) into each bottle; putting the sample bottle into a constant temperature oscillator, wherein the speed of a shaking table is 50rpm, and the temperature is 37 +/-0.5 ℃; precisely absorbing a certain amount of release medium at a preset time, supplementing fresh release medium with the same volume, and measuring the concentration of the drug in the absorbed release solution by high performance liquid chromatography; 3 groups of parallel experiments are carried out on each corresponding electrode; the single release amount, the cumulative release amount and the cumulative release degree of the sample are calculated from the drug concentration, and a cumulative release curve is drawn to form a release behavior determination result, which is shown in fig. 7.

As can be seen from fig. 7, when the drug-carrying part 6 is the same, different sustained-release parts 5 can control the drug release rate (examples #1, #2, #3, # 4); when the sustained-release components 5 are the same, and the drug-carrying components 6 with the same drug type and different drug-carrying capacity are adopted (examples #2 and # 5), the cochlear implant drug-carrying electrode has similar drug-releasing rate and different drug-releasing cycles; the drug-carrying part 6 containing the DA is replaced by the drug-carrying part 6 containing the DSP with high water solubility, so that the drug release concentration can be quickly improved in the early period, and the time for entering the drug release stabilization period is shortened (examples #5 and # 6); by selecting a drug carrying part 6 containing different drug types, simultaneous release of both drugs can be achieved (example # 7).

The clinical application of the cochlear implant drug-loaded electrode is as follows:

referring to the flow chart of fig. 8, the specific process is as follows:

step (1), determining the type, treatment period (short, medium and long), drug release rate, drug concentration and the like of the required drug according to the clinical treatment requirement;

step (2), selecting a medicine carrying component with the corresponding medicine type, medicine carrying amount, shape and size in the step (1);

step (3), selecting a slow-release component with the porosity, the shape and the size corresponding to those in the step (1);

step (4), selecting a cochlear implant electrode which is adaptive to the drug-carrying component in the step (1) and the slow-release component in the step (2);

step (5), loading and packaging the artificial cochlea medicament-carrying electrode;

and (6) implanting the implant through an operation to perform drug slow-release treatment.

Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, while the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims

1. The cochlear implant drug-loaded electrode is characterized by comprising a cochlear implant electrode with a specific structure, a drug-loaded component and a sustained-release component, wherein the cochlear implant electrode with the specific structure is provided with a drug cavity and a sustained-release structure and comprises a flexible electrode tip, n stimulation electrodes, m sustained-release ports, 1 loading port, 1 drug cavity, a silica gel body, a first boosting ring, a second boosting ring, an implanted fin, a wave guide wire bundle, a spiral guide wire bundle, a loop electrode, a stimulation electrode lead and a loop electrode lead, wherein the flexible electrode tip is arranged at the forefront end of the silica gel body, the n stimulation electrodes and the m sustained-release ports are all arranged on the silica gel body, the first boosting ring, the second boosting ring and the implanted fin are arranged behind the flexible electrode tip and the loop electrode lead, the stimulation electrode is connected with the stimulation electrode lead, the loop electrode lead is connected with the loop electrode lead, the stimulation electrode lead forms the wave guide wire bundle and the spiral guide wire bundle in the silica gel body, the drug cavity is arranged in the middle of the silica gel body, the loading port is an inlet of the drug cavity, the first boosting ring is arranged between the first boosting ring and the second boosting ring, and the inner diameter of the drug cavity is larger than that of the silica gel cavity; the shape of the slow release port is matched with that of the slow release component, and the inner diameter of the slow release port is larger than the outer diameter of the slow release component.

2. The cochlear implant electrode of claim 1, wherein the stimulation electrode and the sustained release port are positioned in the same position, staggered in the same position, or staggered in the same position.

3. The cochlear implant drug-carrying electrode according to claim 1, wherein the inner diameter of the drug cavity is 0.01 to 0.05mm larger than the outer diameter of the drug-carrying member, and the inner diameter of the sustained-release port is 0.01 to 0.05mm larger than the outer diameter of the sustained-release member.

4. The cochlear implant drug-loaded electrode according to claim 1, wherein the drug-loaded component comprises 5-95 wt% of a drug-loaded polymer, 5-95 wt% of a drug-loaded adjuvant, and 0-10 wt% of the drug-loaded adjuvant, and the drug-loaded polymer is uniformly dispersed in the drug-loaded component; the slow release component comprises 70-100 wt% of slow release polymer and 0-30 wt% of slow release auxiliary agent.

5. <xnotran> 4 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . </xnotran>

6. The cochlear implant drug-loaded electrode of claim 4, wherein the drug-loaded polymer and the sustained-release polymer are each selected from one or more of polylactide, polyglycolide, glycolide-lactide copolymer, polyethylene glycol, polycaprolactone, L-polylactic acid, poly-4-hydroxybutyrate, and silicone rubber.

7. The cochlear implant drug-loaded electrode of claim 4, wherein the drug-loaded adjuvant and the sustained-release adjuvant are both release regulators or pore-forming agents, and are each selected from one or more of hydroxypropyl methylcellulose, hyaluronic acid and its sodium salt, poloxamer, polyethylene glycol, polyether, polyvinyl alcohol, polyvinylpyrrolidone, lactose, mannitol, glucose, maltose, sorbitol, sodium dodecyl sulfate, sodium chloride, potassium chloride, magnesium carbonate, sodium bicarbonate, potassium bicarbonate or sucrose.

8. A method for manufacturing a cochlear implant electrode according to any of claims 1 to 7, comprising the steps of,

s10, manufacturing a cochlear implant electrode with a specific structure;

s20, manufacturing a medicine carrying part;

s30, manufacturing a slow release component;

the method for manufacturing the cochlear implant electrode with the specific structure comprises the following steps of S10:

s15, sterilizing and packaging;

s24, sterilizing and packaging;

s30, manufacturing a slow-release component, comprising the following steps of:

and S34, sterilizing and packaging.

9. A method for assembling and packaging a cochlear implant electrode according to any of claims 1 to 7, comprising the steps of:

and S5, curing the adhesive.

10. The assembling and packaging method of the cochlear implant drug-loaded electrode according to claim 9, wherein after the drug-loaded part is loaded, the loading port is packaged by a packaging body, and the packaging body is a screw cap or plug made of biocompatible silicone rubber.